The term “controlled release” refers to the release of an agent such as a drug from a composition or dosage form in which the agent is released according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic or diagnostic response as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations. For example, in the treatment of chronic pain, controlled release formulations are often highly preferred over conventional short-acting formulations.
Controlled release pharmaceutical compositions and dosage forms are designed to improve the delivery profile of agents, such as drugs, medicaments, active agents, diagnostic agents, or any substance to be internally administered to an animal, including humans. A controlled release composition is typically used to improve the effects of administered substances by optimizing the kinetics of delivery, thereby increasing bioavailability, convenience, and patient compliance, as well as minimizing side effects associated with inappropriate immediate release rates such as a high initial release rate and, if undesired, uneven blood or tissue levels.
The term “bioavailability” is used to describe the degree to which a drug becomes available at the site(s) of action after administration. The degree and timing in which an agent such as a drug becomes available to the target site(s) after administration is determined by many factors, including the dosage form and various properties such as dissolution rate of the drug. It is well known that some drug compositions suffer from poor bioavailability because of poor solubility of the active ingredient itself.
Numerous methods have been developed for enhancing the bioavailability of poorly soluble drugs. Particle size reduction, such as nanoparticulate forms of the agent, is one such method since the dissolution rate of a compound is related to the particle size. A nanoparticle is a sub-micron particle, the size of which is measured in nanometers (having at least one dimension of less than 100 nanometers). Nanoparticulate compositions comprise poorly water-soluble drug or agent particles having an extremely small particle size, i.e., less than one micron. With a decrease in particle size, and a consequent increase in ratio of surface area/mass, a composition tends to be rapidly dissolved and absorbed following administration. For certain formulations, this characteristic can be highly desirable, as described, for example, in U.S. Pat. Nos. 5,145,684; 5,510,118; 5,534,270; and 4,826,689; which are specifically incorporated by reference. However, rapid dissolution is contrary to the goal of controlled release.
Emulsion polymerization is a popular and well-known polymerization method for preparing uniform polymeric microspheres composed of relatively hydrophobic monomers (Esumi, K., Polymer Interfaces and Emulsions, Marcel Dekker, New York, 1999). Usually, this polymerization system consists of a hydrophobic monomer, water, and emulsifier such as a sodium salt of long-chain aliphatic acids and a water-soluble initiator. Nevertheless, factors such as nucleation and stability of the particles, and emulsification of the monomer droplets, not only during the polymerization process but also during the shelf life of the preparations, could be affected because of the presence of the surfactant (Unzue, M. et al., J. Appl. Polym. Sci., 1997, 66:1803). Any unbound surfactant can migrate, forming aggregates that increase the sensitivity of the product and cause plasticization by water (Schoonbrood, H. and Asua, J. M., Macramolecules, 1997, 30:6034) and other undesirable effects on the stability and effectiveness of the products. A potential solution involves using reactive surfactants to assure that all of the surfactant is bound covalently to the polymer material and not present in unbound form in the aqueous media. It has been reported that migration of unbound surfactant can modify adhesion, water sensitivity and the optical properties, affecting the stability of the emulsion, especially when it is used as a drug delivery system.